TY - JOUR
T1 - Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1
AU - Chalkiadaki, Kleanthi
AU - Hooshmandi, Mehdi
AU - Lach, Gilliard
AU - Statoulla, Elpida
AU - Simbriger, Konstanze
AU - Amorim, Ines S
AU - Kouloulia, Stella
AU - Zafeiri, Maria
AU - Pothos, Panagiotis
AU - Bonneil, Éric
AU - Gantois, Ilse
AU - Popic, Jelena
AU - Kim, Sung-Hoon
AU - Wong, Calvin
AU - Cao, Ruifeng
AU - Komiyama, Noboru H
AU - Atlasi, Yaser
AU - Jafarnejad, Seyed Mehdi
AU - Khoutorsky, Arkady
AU - Gkogkas, Christos G
N1 - © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2022/10/31
Y1 - 2022/10/31
N2 - MAPK (mitogen-activated protein kinase) interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterised substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that whereas deletion of Mnk1/2 (Mnk DKO) impairs synaptic plasticity and memory in mice, ablation of phosho-eIF4E (Ser209) does not affect these processes, suggesting that Mnk1/2 possess additional downstream effectors in the brain. Translational profiling revealed only a small overlap between Mnk1/2- and phospho-eIF4E(Ser209)-regulated translatome. We identified the synaptic Ras GTPase activating protein 1 (Syngap1), encoded by a syndromic autism gene, as a downstream target of Mnk1 since Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk DKO mice. Knock-down of Syngap1 reversed memory deficits in Mnk DKO mice, and pharmacological inhibition of Mnks rescued autism-related phenotypes in Syngap1+/- mice. Thus, Syngap1 is a downstream effector of Mnk1, and the Mnks-Syngap1 axis regulates memory formation and autism-related behaviours.
AB - MAPK (mitogen-activated protein kinase) interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterised substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that whereas deletion of Mnk1/2 (Mnk DKO) impairs synaptic plasticity and memory in mice, ablation of phosho-eIF4E (Ser209) does not affect these processes, suggesting that Mnk1/2 possess additional downstream effectors in the brain. Translational profiling revealed only a small overlap between Mnk1/2- and phospho-eIF4E(Ser209)-regulated translatome. We identified the synaptic Ras GTPase activating protein 1 (Syngap1), encoded by a syndromic autism gene, as a downstream target of Mnk1 since Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk DKO mice. Knock-down of Syngap1 reversed memory deficits in Mnk DKO mice, and pharmacological inhibition of Mnks rescued autism-related phenotypes in Syngap1+/- mice. Thus, Syngap1 is a downstream effector of Mnk1, and the Mnks-Syngap1 axis regulates memory formation and autism-related behaviours.
U2 - 10.1093/brain/awac398
DO - 10.1093/brain/awac398
M3 - Article
C2 - 36315645
JO - Brain
JF - Brain
SN - 0006-8950
ER -